UC San Diego

The circadian clock drives the timing of many biological processes, from molecular dynamics of gene regulation and protein synthesis to animal behavior. Cell- and region-autonomous circadian oscillators within the brain are not well understood; however, it is known that circadian rhythm dynamics are pivotal to health, as circadian rhythm disruptions are a major hallmark symptom and driver of a range of neurological diseases. Additionally, dysregulated circadian rhythmicity is a key feature of advancing age, and may contribute to pathological aging. Alzheimer’s disease (AD) is a slowly progressing, debilitating neurodegenerative disorder affecting over 50 million people globally. AD is a disease of aging; however, the insidious pathological processes driving the disease are thought to begin decades before individuals show severe cognitive impairments. Some of the major and most disruptive symptoms of AD are disruptions in circadian rhythms, including impairment in sleep and daily rhythms in behavior and activity. This dissertation aims to characterize patterns of circadian gene regulation across the mouse brain under healthy conditions as well as in the context of pathological aging and Alzheimer’s disease using novel spatial transcriptomic technology, with the goal of bettering our understanding of region-specific circadian disruption as it relates to vulnerability to pathological aging and AD. In Chapter 1, I detail our work characterizing rhythmicity across the brain using spatial transcriptomics. In Chapter 2, I explore region-specific patterns in rhythmic gene expression in middle-aged mice compared to young adult mice to identify regional vulnerability to aging in the context of circadian rhythm disruption. In Chapter 3, I use a mouse model of AD to investigate region-specific patterns in differential rhythmic gene expression to identify AD pathology early and late into disease progression. Altogether this work shows that rhythmic patterns of gene expression vary across the mouse brain and provides evidence for the first time, that these patterns become disrupted in a region-dependent manner early in the course of aging and AD progression. This work has important implications for early identification and potential disease modifying treatments of AD and other diseases of aging.